Basic Research
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2005; 11(8): 1122-1130
Published online Feb 28, 2005. doi: 10.3748/wjg.v11.i8.1122
Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells
Elisabetta Ceni, Tommaso Mello, Mirko Tarocchi, David W Crabb, Anna Caldini, Pietro Invernizzi, Calogero Surrenti, Stefano Milani, Andrea Galli
Elisabetta Ceni, Stefano Milani, Mirko Tarocchi, Calogero Surrenti, Andrea Galli, Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy
David W Crabb, Departments of Medicine and of Biochemistry and Molecular Biology, Indiana University School of Medicine, IN, USA
Anna Caldini, Clinical Chemistry Laboratories, Careggi Hospital, Florence, Italy
Pietro Invernizzi, Department of Medicine Ospedale San Paolo, University of Milan, Milan, Italy
Tommaso Mello, Farmacogenomic Foundation FiorGen, Florence, Italy
Author contributions: All authors contributed equally to the work.
Correspondence to: Andrea Galli, M.D., Ph.D., Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Morgani 85, 50134 Firenze Italy.
Telephone: +39-554271294 Fax: +39-554271297
Received: July 9, 2004
Revised: July 12, 2004
Accepted: October 13, 2004
Published online: February 28, 2005

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor γ (PPARγ), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma.

METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARγ was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARγ activity was evaluated by transient reporter gene assay. Flow cytometry and DNA fragmentation assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot.

RESULTS: Exposure to TZD inhibited colony formation in a PPARγ-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate.

CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pacreatic ductal differentiation.

Keywords: Thiazolidinediones, Pancreatic cancer, PPARγ, Cancer growth, Differentiation